The application of ATR-FTIR spectroscopy and multivariate data analysis to study drug crystallisation in the stratum corneum

Drug permeation through the intercellular lipids, which pack around and between corneocytes, may be enhanced by increasing the thermodynamic activity of the active in a formulation. However, this may also result in unwanted drug crystallisation on and in the skin. In this work, we explore the combination of ATR-FTIR spectroscopy and multivariate data analysis to study drug crystallisation in the skin. Ex vivo permeation studies of saturated solutions of diclofenac sodium (DF Na) in two vehicles, propylene glycol (PG) and dimethyl sulphoxide (DMSO), were carried out in porcine ear skin. Tape stripping and ATR-FTIR spectroscopy were conducted simultaneously to collect spectral data as a function of skin depth. Multivariate data analysis was applied to visualise and categorise the spectral data in the region of interest (1700-1500cm(-1)) containing the carboxylate (COO(-)) asymmetric stretching vibrations of DF Na. Spectral data showed the redshifts of the COO(-) asymmetric stretching vibrations for DF Na in the solution compared with solid drug. Similar shifts were evident following application of saturated solutions of DF Na to porcine skin samples. Multivariate data analysis categorised the spectral data based on the spectral differences and drug crystallisation was found to be confined to the upper layers of the skin. This proof-of-concept study highlights the utility of ATR-FTIR spectroscopy in combination with multivariate data analysis as a simple and rapid approach in the investigation of drug deposition in the skin. The approach described here will be extended to the study of other actives for topical application to the skin

Amplification and next generation sequencing of near full-length human enteroviruses for identification and characterisation from clinical samples

© 2018, The Author(s). More than 100 different enterovirus (EV) genotypes infect humans and contribute to substantial morbidity. However, current methods for characterisation of full-length genomes are based on Sanger sequencing of short genomic regions, which are labour-intensive and do not enable comprehensive characterisation of viral populations. Here, we describe a simple and sensitive protocol for the amplification and sequencing of near full-length genomes of human EV species using next generation sequencing. EV genomes were amplified from 89% of samples tested, with Ct values ranging between 15.7 and 39.3. These samples included 7 EV-A genotypes (CVA2, 5–7, 10, 16 and EV71), 19 EV-B genotypes (CVA9, CVB1-6, ECHO3, 4, 6, 7, 9, 11, 16, 18, 25, 29, 30, and EV69), 3 EV-C genotypes (CVA19 and PV2, 3) and 1 EV-D genotype (EV70). We characterised 70 EVs from 58 clinical stool samples and eight reference strains, with a minimum of 100X depth. We found evidence of co-infection in four clinical specimens, each containing two distinct EV genotypes (CVB3/ECHO7, CVB3/ECHO18 and ECHO9/30). Characterisation of the complete genome provided conclusive genotyping of EVs, which can be applied to investigate the intra-host virus evolution of EVs, and allows further identification and investigation of EV outbreaks

Growth from birth to 6 months of infants with and without intrauterine preeclampsia exposure

Intrauterine preeclampsia exposure affects the lifelong cardiometabolic health of the child. Our study aimed to compare the growth (from birth to 6 months) of infants exposed to either a normotensive pregnancy or preeclampsia and explore the influence of being born small for gestational age (SGA). Participants were children of women participating in the Post-partum, Physiology, Psychology and Paediatric follow-up cohort study. Birth and 6-month weight and length z-scores were calculated for term and preterm (<37 weeks) babies, and change in weight z-score, rapid weight gain (≥0.67 increase in weight z-score) and conditional weight gain z-score were calculated. Compared with normotensive exposed infants (n = 298), preeclampsia exposed infants (n = 84) were more likely to be born SGA (7% versus 23%; P < 0.001), but weight gain from birth to 6 months, by any measure, did not differ between groups. Infants born SGA, irrespective of pregnancy exposure, were more likely to have rapid weight gain and had greater increases in weight z-score compared with those not born SGA. Preeclampsia exposed infants born SGA may benefit from interventions designed to prevent future cardiometabolic disease

Nano-thermal imaging of the stratum corneum and its potential use for understanding of the mechanism of skin penetration enhancer

Nano-thermal analysis (nano-TA) is a localised thermal technique which maps a surface in terms of thermal transitions by combining atomic force microscopy with the use of thermal probes, allowing a spatial resolution of sub–100 nm. In this communication, we describe the application of a localised nano-TA approach, transition temperature microscopy (TTM), to investigate the thermotropic properties of porcine stratum corneum (PSC) as a function of depth and the influence of penetration enhancer on the nano-thermal properties of PSC. The investigations were conducted on PSC removed using tape strips. The transition temperature of PSC recorded at ∼220 °C was ascribed to protein denaturation/degradation. A decrease in the transition temperature was observed with an increase of skin depth. ‘Transition depression’ was observed when PSC was treated with propylene glycol, suggesting its water extraction effect on SC protein and a drop in the biomechanical properties of the SC. TTM has the potential to be extended to on in situ investigations of various penetration enhancers

An exploratory cluster randomised trial of a university halls of residence based social norms marketing campaign to reduce alcohol consumption among 1st year students

&lt;p&gt;Aims: This exploratory trial examines the feasibility of implementing a social norms marketing campaign to reduce student drinking in universities in Wales, and evaluating it using cluster randomised trial methodology.&lt;/p&gt; &lt;p&gt;Methods: Fifty residence halls in 4 universities in Wales were randomly assigned to intervention or control arms. Web and paper surveys were distributed to students within these halls (n = 3800), assessing exposure/contamination, recall of and evaluative responses to intervention messages, perceived drinking norms and personal drinking behaviour. Measures included the Drinking Norms Rating Form, the Daily Drinking Questionnaire and AUDIT-C.&lt;/p&gt; &lt;p&gt;Results: A response rate of 15% (n = 554) was achieved, varying substantially between sites. Intervention posters were seen by 80% and 43% of students in intervention and control halls respectively, with most remaining materials seen by a minority in both groups. Intervention messages were rated as credible and relevant by little more than half of students, though fewer felt they would influence their behaviour, with lighter drinkers more likely to perceive messages as credible. No differences in perceived norms were observed between intervention and control groups. Students reporting having seen intervention materials reported lower descriptive and injunctive norms than those who did not.&lt;/p&gt; &lt;p&gt;Conclusions: Attention is needed to enhancing exposure, credibility and perceived relevance of intervention messages, particularly among heavier drinkers, before definitive evaluation can be recommended. A definitive evaluation would need to consider how it would achieve sufficient response rates, whilst hall-level cluster randomisation appears subject to a significant degree of contamination.&lt;/p&gt

Virtual signatures of dark sectors in Higgs couplings

Where collider searches for resonant invisible particles loose steam, dark sectors might leave their trace as virtual effects in precision observables. Here we explore this option in the framework of Higgs portal models, where a sector of dark fermions interacts with the standard model through a strong renormalizable coupling to the Higgs boson. We show that precise measurements of Higgs-gauge and triple Higgs interactions can probe dark fermions up to the TeV scale through virtual corrections. Observation prospects at the LHC and future lepton colliders are discussed for the so-called singlet-doublet model of Majorana fermions, a generalization of the bino-higgsino scenario in supersymmetry. We advocate a two-fold search strategy for dark sectors through direct and indirect observables.Comment: 20 pages, 7 figures, 1 tabl

A powerful bursting radio source towards the Galactic Centre

Transient astronomical sources are typically powered by compact objects and usually signify highly explosive or dynamic events. While radio astronomy has an impressive record of obtaining high time resolution observations, usually it is achieved in quite narrow fields-of-view. Consequently, the dynamic radio sky is poorly sampled, in contrast to the situation in the X- and gamma-ray bands in which wide-field instruments routinely detect transient sources. Here we report a new transient source, GCRT J1745-3009, detected in 2002 during a moderately wide-field radio transient monitoring program of the Galactic center (GC) region at 0.33 GHz. The characteristics of its bursts are unlike those known for any other class of radio transient. If located in or near the GC, its brightness temperature (~10^16 K) and the implied energy density within GCRT J1745-3009 vastly exceeds that observed in most other classes of radio astronomical sources, and is consistent with coherent emission processes rarely observed. We conclude that GCRT J1745-3009 is the first member of a new class of radio transient sources, the first of possibly many new classes to be identified through current and upcoming radio surveys.Comment: 16 pages including 3 figures. Appears in Nature, 3 March 200

How Does Blood-Retinal Barrier Breakdown Relate to Death and Disability in Pediatric Cerebral Malaria?

BACKGROUND: In cerebral malaria, the retina can be used to understand disease pathogenesis. The mechanisms linking sequestration, brain swelling and death remain poorly understood. We hypothesized that retinal vascular leakage would be associated with brain swelling. METHODS: We used retinal angiography to study blood-retinal barrier integrity. We analyzed retinal leakage, histopathology, brain MRI, and associations with death and neurological disability in prospective cohorts of Malawian children with cerebral malaria. RESULTS: Three types of retinal leakage were seen: Large focal leak (LFL), punctate leak (PL) and vessel leak. LFL and PL were associated with death (OR 13.20, 95%CI 5.21-33.78 and 8.58, 2.56-29.08 respectively), and brain swelling (p<0.05). Vessel leak and macular non-perfusion were associated with neurological disability (3.71, 1.26-11.02 and 9.06, 1.79-45.90). LFL was observed as an evolving retinal hemorrhage. A core of fibrinogen and monocytes was found in 39 (93%) white-centered hemorrhages. CONCLUSIONS: Blood-retina barrier breakdown occurs in three patterns in cerebral malaria. Associations between LFL, brain swelling, and death suggest that the rapid accumulation of cerebral hemorrhages, with accompanying fluid egress, may cause fatal brain swelling. Vessel leak from barrier dysfunction, and non-perfusion were not associated with severe brain swelling, but with neurological deficits, suggesting hypoxic injury in survivors